This proposal has as its central purpose the establishment of a long-term research effort into the molecular pathology of cellular aging in the brain. We seek to understand the role of a major class of neuronal proteins, the fibrous proteins, both in normal aging and in the pathogenesis of the late-life dementias. In a society in which the average age and expected lifespan have climbed dramatically, a surprisingly modest investigative effort has heretofore been directed at applying the tools of modern cell biology to understanding neuronal senescence. By far the most common neuronal degenerations that accompany aging are presenile and senile dementia. These age-related disorders, which are now classified together under the eponymic term Alzheimer's Disease, have as their most widespread and specific pathological finding an abnormality of the neuronal fibrous proteins, seen both in the perikarya and the neuropil. Fibrillary degeneration of neurons and their processes is associated not only with progressive loss of intellect but represents the most important structural abnormality in the brains of healthy individuals of great age. For these reasons, we propose to isolate and biochemically characterize the filamentous proteins which are found in Alzheimer's Disease and to compare them with analogous proteins in the brains of elderly patients with normal mentation and in an intriguing experimental model of neurofibrillary disease, aluminum encephalopathy. We will use such techniques as neuronal/glial isolation, high resolution analytical protein separation, immunohistochemistry and electron microscopy to begin to clarify the role of these proteins in aging of the brain and in senile dementia, the pathogenesis of which is at present totally unexplained.